The goal of this program project is to gain a better understanding of the relationship between the persistence of neurotropic virus and the development of neurologic disease in the elderly. The proposed studies center on four highly neurotropic viruses from two families (herpesviruses and picornaviruses) that are associated with serious morbidity and occasional mortality in the elderly. Human and animal subjects will be studies clinically and by using virologic, molecular, and immunologic techniques. We will prospectively study the association of morbidity in the aging with varicella-zoster virus (VZV) persistence. We will also prospectively analyze immune responsiveness to virus in both the elderly and young adult with and without disease. We will study molecular restriction of herpes virus in the nervous system and age-related dysfunction in response to virus infection. We will carry out a molecular analysis of wild and mutant polioviruses and study the influence of age on pathogenesis. Finally in an attempt to eradicate VZV-induced disease in the elderly, we will vaccinate a trial population with live virus vaccine and study their immune response. At the same time, a complete library of VZV genes will be developed, and VZV glycoprotein genes will be cloned into vectors and the expressed genes will be studied immunologically. This proposal melds the skills and strategies of investigators with expertise in neurology, dermatology, preventive medicine, aging, molecular virology, immunology, genetics and clinical investigation. This concentrated effort is focused on prospective studies towards determining the pathogenesis and eventual prevention of viral diseases of the nervous system in the elderly.